WEEK 9 Antimicrobial chemotherapy.ppt

5/19/2018 WEEK 9 Antimicrobial chemotherapy.ppt

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ANTIBACTERIAL

CHEMOTHERAPY


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Antibacterial chemotherapy OUT

COMES

By the end of the sessions, learners willbe able to:

escribe the mode of actions of antibacterial

chemotherapeutic agents

iscuss antibiotic susceptibility testing

Identify the complications of chemotherapy

escribe the mechanisms of bacterial

resistance to antimicrobial agents


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Definitions:

-

Antimicrobial chemotherapeutic agents:chemically synthesized substances that are used to

treat infectious diseases by killing or inhibiting the

growth of microorganisms.

- Antibiotics:

antimicrobial substances that are produced as

secondary metabolites by certain groups ofmicroorganisms (Streptomyces, Bacillus, few moulds

as penicillum and Cephalosporium).


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Types of antimicrobials (concerning the

nature)

Natural antibiotics: original source was micro-organisms.

Semisynthetic antibiotics: by chemicalmodification of certain antibiotics to achieve the

desired properties.

Fully synthetic antibiotics: higher generations.


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Types of actions of antibiotics

1- Bacteriostatic agent:

Antimicrobial agent capable of inhibiting

bacterial multiplication.

2- Bactericidal agent:

Antimicrobial agent capable of killingbacteria.


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The ability of an antimicrobial agent toharm a pathogen without harming thehost. It may be a function of:

1- A specific receptor or target (found inmicrobe but not in human body)

2- Inhibition of a biochemical reaction(essential for microbe but not for the host)

Selective toxicity


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Spectrum of activity of antibiotic:

The range of microorganisms that are affected by a certainantibiotic is expressed as its spectrum of action.

1- Broad spectrumantibiotics:

antibiotics that kill or inhibit the growth of a wide range ofGm +ve & Gm ve bacteria.

2- Narrow spectrumantibiotics:antibiotics that are effective mainly against either gm +ve or

Gm ve bacteria.

3- Limited or mono spectrum antibiotics:antibiotics that are effective only against a single organism

or disease


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MECHANISMS OF ACTION OF

ANTIMICROBIAL DRUGS

1- Inhibition of bacterial cell wall

synthesis

2- Interference with the cell membranefunction.

3- Inhibition of bacterial protein

synthesis.4- Inhibition of bacterial nucleic acid

synthesis (DNA or RNA).


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1- Inhibition of bacterial wall synthesis

These antibiotics are bactericidal with minimal tissue

toxicity.

Members: a--lactam antibioticsb - Glycopeptides

c - Cycloserine and bacitracin- -lactams inhibit the last steps of PG synthesis, while

Glycopeptides & cycloserine inhibit the early steps.

2- interference with cell membrane function These antibiotics are bactericidal & highly toxic.

Members: - Polymyxin, colistin

They cause cell membrane disruption &

interfere with its function


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3- Inhibition of bacterial protein synthesis:

Bacteriahave 70S ribosomes (with 30S & 50S subunits)

Agents acting on 30S subunit:

- Tetracycline

- Aminoglycosides (gentamycin, streptomycin, amikacin)

Agents acting on the 50S subunit:

- Macrolides (erythromycin, azethromycin)

- Lincomycins

- Streptogramins

- linezolid

- Chloramphenicol - Fusidic acid


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4- Inhibition of nucleic acid synthesis:

This may occur by:

A- Inhibition of mRNAsynthesis (e.g. rifampin)

B- Inhibition of DNAsynthesis (e.g. quinolones)

C- Inhibition of dihydrofolic acid reductaseleading toinhibition of folic acid which is important for purine synthesis

and consequently nucleic acid formation (e.g.

trimethoprim).

D- Inhibition of folic acid synthesis by competitiveantagonism (e.g. sulphonamides). This drug is a structural

analogue for PABA (para-amino benzoic acid) a compound

which is essential for the synthesis of folic acid.


12/25MECHANISMS OF ACTION OF Antibiotics


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Choice of an Antimicrobial Agent for

Therapy

1- Can penetrate to the site of infectionin a proper

concentration.

2-Know the nature of the infection.

3-Give the appropriate doseof the antibiotic for the properduration

4- Choose the spectrumof antibiotic activity.

5- Know the potential of the drug to produce toxicity anduse antibiotics that are only safefor the pregnantand

lactating women and for infantsand children.

6- Choose bactericidalantibiotics.


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Microbial Susceptibilities to Antimicrobial

Agents

Ideally, the appropriate antibioticto treat any infection

should be determined in vitro before being given.

The in vivo activity of an antimicrobial agent is not

always the same as its in vitrosusceptibility due theinvolvement of many host factors.

The activityof an antimicrobial agent against an

organism depends on its concentration.

The minimal inhibitory concentration (MIC) isdefined asthe lowest concentration of the drug that

prevents the growth of a test organism.


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The routine in vitro susceptibility testing can

be done by one of the following methods:

1. Disc diffusion methods.

2. Dilution methods such as tube broth

dilution.

3. Gradient diffusion (E-test) methods.


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Disc Diffusion E test method

method


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Empiric therapy

It is the best guess procedure based upon aprovisional diagnosis made by the physician that a patienthas a bacterial infection which requires treatment.

Depending on the type of infection, there will be a short list

of bacteria probably causing that infection.

Depending on the type of bacteria, there will be an antibiotic

most likely to successfully treat that infection.

Indications:1- In seriously ill patients empiric therapy should be started

without delay but after collecting specimens for culture.

2- In closed lesions where there is no available sample.


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Combined Therapy

-Definition:the use of more than one antibiotic in order toachieve successful clinical response.

- N.B.: The rule in treatment is monotherapy.

- Indications of combined chemotherapy:1- Serious infections (e.g. meningitis).

2- Infection with Mycobacterium tuberculosis.

3- Febrile neutropenia.

4-To delay development of drug-resistant mutants.

5- Mixed infections.


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Complications of Chemotherapy

1- Toxicity:

- tetracycline may cause staining of teeth in infants.- Streptomycin may affect the 8thcranial nerve.

- Aminoglycosides may cause nephrotoxicity.

- Chloramphenicol can cause bone marrow depression.

2- Allergy (hypersetivinsity):- Penicillin may cause urticaria, anaphylactic shock.

- Local application of sulphonamides may result in contact dermatitis.

3- Emergence of resistant strains:

- The abuse of antibiotics (low dosage, interrupted course, noreal indication, improper choice) encourage the emergence of resistantmutants.

4- Superinfection:- Occurs as a result of outgrowth of resistant members of normalflora when the sensitive ones are eradicated during antibiotic therapy.


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RESISTANCE TO ANTIMICROBIAL AGENTS

Antibiotic resistant is a global problem faced today in the treatment

of infectious diseases. It is more prevalent in hospitals especially intensive care units due to

higher antibiotic use.

Categories of Resistance to antimicrobial agents:

I- Intrinsic (inherent or natural) resistance.- Bacteria are insensitive naturally to antibiotics without acquisition

of resistance factors.

- It is consistent & can be expected once the organism is known.

- Examples: - Streptomycetes are protected from the antibiotics they

produce.

- An organism lacks the target for the antibiotic as in wall-

less bacteria to cell wall inhibitor antibiotica.


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RESISTANCE TO ANTIMICROBIAL AGENTS

II- Acquired resistance: It results from altered bacterial physiology and structure due

to changes in the genome of the organism.

It is inconsistent and unpredictable.

The acquired resistance mechanisms are driven by 2 geneticprocesses in bacteria:

(1) Mutation: the more frequent the exposure to theantibiotic, the greater the potential resistance.

(2) Exchange of genes between strains and species that canbe encoded on plasmid, phage or others.


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PLASMID

Extrachromosomal, small,

cicular, double-stranded DNA

Function:

Antibiotic resistance


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Mechanisms of Acquired Resistance to

antimicrobial agents

1-Reduction of the intracellular concentration of theantibiotic:

- either by decrease in influx of antibiotic via the bacterial cellwall or

- Efflux pumps: the antibiotic is pumped out through the cellmembrane faster than it can diffuse in which reduces itsconcentration.

2-Inactivation of the antibiotic: e.g.:- Production of -lactamases that hydrolyse -lactam ring in

penicillins & cephalosporins.

- Production of aminoglycoside modifying enzymes.


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Mechanisms of Acquired Resistance to

antimicrobial agents

3-Target modification: modification of the target sitefor the antibiotic results in reduced affinity for thisreceptor, e.g.:

- Alteration of the PBPs leads to resistance to -lactam

antibiotics.- Alteration of the 50S or 30S ribosomal subunits

reduces the affinity of the antibiotics targetingthese structures.

4-Target elimination by developing newmetabolic pathways:

- These bacteria have the ability to create newmetabolic pathway that bypass the original target


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ANTIMICROBIAL CHEMOPROPHYLAXIS

-Definition:

Administration of an effective antimicrobial agent toprevent infection with a certain microbe.

- Indications:

1- Examples of Surgical indications:

Preoperative in some surgical operations.

2-Examples of Medical indications:

a- In rheumatic fever.

b- In meningococcal meningitis.

c- In subacute bacterial endocarditis.

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